Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and ranks seventh in terms of global morbidity and mortality. Patients with bilateral pulmonary tuberculosis (TB), cavitary disease, and persistently positive sputum smears pose a special risk for treatment failure and/or relapse. Under HL59832 we treated 11 active pulmonary TB patients with rIFN-gamma aerosol for one month, noting improvements in symptoms, chest radiographs, and declines in inflammatory cytokines. Also, there were striking declines in HIV-1 viral burdens in 5/5 HIV- l/TB coinfected patients. In bronchoalveolar lavage (BAL) cells we observed increased STAT-1 binding and IRF-1 and -9 binding activity post treatment. In preliminary data, we have been able to identify gene clusters induced/repressed in BAL cells by short-term rIFN-gamma aerosol treatment. Our goal is to now demonstrate clinical efficacy of long-term rIFN-gamma aerosol treatment in advanced, cavitary pulmonary TB, where the risk of failure/relapse is unusually high with standard treatment. We propose in Aim 1 a randomized, controlled clininical trial in 64 patients in a NYU/Bellevue - University of Cape Town subcontract using rIFN-gamma aerosol for 4 months in addition to standard treatment compared to standard treatment alone. Endpoints include percent failure/relapse, time to culture Mtb (including negative culture), and change in cavity size/CT-scan findings. In Aim 2 we will evaluate the Thl response in blood and lung using flow cytometry, cytokine measurements and in vitro TB antigen challenge to characterize macrophage and lymphocyte responses to 4 months rIFN-gamma. In Aim 3 we will endeavor to determine the molecular effects of aerosolized rIFN-gamma on TGF-beta, its receptor, and Smad signaling molecules, and downstream effectors including collagen, MMP1 and 9, and CTGF using real-time PCR, EMSAs, and immunoblots with Richard Pine, PhD (subcontract to the Public Health Research Institute). In Aim 3b we will pursue functional genomics to identify novel human gene targets of rIFN-gamma aerosol and DOTS during the course of treatment. This study is critical in developing efficacious treatment strategies for TB and demonstrating that rIFN-gamma ameliorates the lung fibrosis and destruction in advanced TB.